Predictive value of DNA repair gene expression for response to neoadjuvant chemotherapy in breast cancer.
Authors: Maximiliano Cassilha Kneubil, Karen Olivia Bazzo Goulart, Janaina Brollo, Guilherme Portela Coelho, Jovana Mandelli, Bruna Caroline Orlandin, Leandro Luis Corso, Mariana Roesch-Ely, João Antônio Pêgas Henriques
Journal: Journal of Clinical Oncology (2022)

e12538 Background: Genome-wide analysis using microarrays has revolutionized the field of breast cancer (BC) research, classifying breast cancer by gene expression profiling. In patients with BC, a substantial body of evidence supports the clinical utility of gene expression profiling. For example, the 21-gene assay (Oncotype DX) and 70-gene assay (MammaPrint) predict BC recurrence and the magnitude of chemotherapy benefit. However, there is currently no gene-expression profiling able to predict chemosensitivity and chemoresistance to neoadjuvant chemotherapy (NACT) during BC treatment. Therefore, the development of specific predictive biomarkers for chemoresistance and chemosensitivity is desirable. In the present study, we explored the predictive value of DNA repair gene expression for response to NACT in BC by evaluating the mRNA expression of 11 selected genes which have a key role in DNA repair mechanisms. Methods: We selected 98 patients with BC treated with NACT. We assessed DNA repair expression in 98 formalin-fixed, paraffin-embedded core biopsy fragments used at diagnosis and in 32 formalin-fixed, paraffin-embedded post-NACT residual tumors using quantitative reverse transcription-polymerase chain reaction. The following genes were selected: BRCA1, PALB2, RAD51C, BRCA2, ATM, FANCA, MSH2, XPA, ERCC1, PARP1 and SNM1. We used the mean of 2 reference genes (GAPDH and ACTB) to minimize the risk of normalization bias that can result from variations in the expression of any single reference gene. Results: Of 98 patients, 33 (33.7%) achieved pathologic complete response (pCR). The DNA expression of 2 genes assessed in pre-NACT biopsies (PALB2 and ERCC1) was lower in pCR than in non-pCR patients (p=0.005 and p=0.009, respectively). After adjustment for tumor grade and molecular subtype, a linear regression model with rank transformation showed that the DNA expression of 2 genes (PALB2 and ERCC1) assessed in pre-NACT biopsies was lower in the pCR group than in the non-pCR group (p=0.014 and p=0.040 respectively). The genes BRCA2 (p=0.009), ATM (p=0.004), FANCA (p=0.001), and PARP1 (p=0.011) showed a lower expression in post-NACT residual tumor samples (n=32) than in pre-NACT biopsy samples (n=98). Conclusions: In the genomics era, treatment should be tailored to the individual patient. The present study showed that PALB2 and ERCC1 expressions, assessed in pre-NACT biopsies, were lower in pCR patients. These alterations in DNA repair could be considered suitable targets for cancer therapy. In addition, BRCA2, ATM, FANCA, and PARP1 expressions were lower in post-NACT residual tumor samples than in pre-NACT biopsies. The use of recently developed multiparameter gene-expression assays, based on the expression of genes involved in different DNA repair pathways, should be further explored in future studies, as they may facilitate the selection of patients most likely to benefit from NACT.